Research Papers:
Ginkgetin induces autophagic cell death through p62/SQSTM1-mediated autolysosome formation and redox setting in non-small cell lung cancer
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Abstract
Jian-Shu Lou1,2, Wen-Chuan Bi1,2, Gallant K.L. Chan1,2, Yan Jin1,2, Chau-Wing Wong2, Zhong-Yu Zhou2, Huai-You Wang1,2, Ping Yao2, Tina T.X. Dong1,2 and Karl W.K. Tsim1,2
1Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China
2Division of Life Science, Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
Correspondence to:
Karl W.K. Tsim, email: [email protected]
Keywords: autophagy, natural compounds, non-small cell lung cancer, p62, mTORC1
Received: July 12, 2017 Accepted: August 27, 2017 Published: October 16, 2017
ABSTRACT
Promoting cell death by autophagy could be a novel treatment for cancer. The major player in autophagy, p62, serves as a good therapeutic target. Ginkgetin, a biflavonoid from Ginkgo biloba leaves, exhibited promising anticancer activity in non-small cell lung cancer cell lines, with an IC50 lower than that of cisplatin. This anticancer effect of ginkgetin was illustrated in a xenograft nude mouse model. Ginkgetin induced autophagic cell death in A549 cells, and this effect was markedly reversed by chemical and genetic approaches. Ginkgetin showed potential binding affinity to p62. Upregulation of p62 through chemical and genetic means decreased cell death, lysosome acidification, and autophagosome formation, which consequently disrupted autolysosome formation. In addition, the decreased autophagy induced by p62 overexpression increased Nrf2/ARE activity and the oxygen consumption rate and decreased on formation of reactive oxygen species. These phenomena were exhibited in a reciprocal manner when p62 was knocked down. Thus, p62 may be a potential target in ginkgetin-induced autophagic cell death, and ginkgetin could be developed as a novel anticancer drug.
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PII: 21862